Chronic inflammation in response to persistent virus infection is associated with autoimmune disease. Patients with autoimmune disease often exhibit dysregulated expression of anti-viral cytokines, including the interferon (IFN) system, however the mechanisms linking persistent virus infection and autoimmunity remain poorly defined. The TNF receptor superfamily member, Lymphotoxin-? receptor (LT?R) and its related signaling pathways, control lymphoid tissue homeostasis and are essential for host innate and adaptive defenses to herpesviruses. The LT?R is a critical pathway for the initial induction of the type I IFN (IFN??) in response to human or mouse cytomegalovirus. In mice, the LT-IFN axis is essential for lymphocyte survival during CMV infection and is mediated between naive B lymphocytes acting as innate effectors that induce IFN?? in virus-infected LT?R+ stromal cells in lymphoid tissues. The TNFR superfamily member, herpesvirus entry mediator (HVEM), and its unconventional ligands, BTLA and CD160, both Ig superfamily members, counter regulate the LT?R pathway and functions as an inhibitory cosignaling pathways for T and B cells. Diverse viruses from herpesviruses to retroviruses have evolved specific mechanisms that modulate LT?R and HVEM-BTLA systems. We hypothesize that viral targeting of the LT?R-IFN axis in persistent infections may disrupt immune homeostasis, promoting the development of autoimmune disease. In this project, we seek to define the LT?R and HVEM-BTLA pathways that regulate the IFN system in response to CMV infection in human and mouse models. Our goal is to develop counter strategies by understanding and altering immune evasion mechanisms. We developed new molecular reagents to specifically probe the LT-IFN and HVEM-BTLA pathways, and engineered viral mutants to use in different mouse genetic models to address the regulation of the LT-IFN system. We have established a highly interactive group of virologists and autoimmune disease specialists as collaborators to assist in the experimental approach and data analysis.